PET and MR imaging in Parkinson’s disease patients with cognitive impairment. A study of dopaminergic dysfunction, amyloid deposition, cortical hypometabolism and brain atrophy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by a severe loss of substantia nigra dopaminergic neurons leading to dopamine depletion in the striatum. PD affects movement, producing motor symptoms such as rigidity, tremor and bradykinesia. Non-motor symptoms include autonomic dysfunction, neurobehavioral problems and cognitive impairment, which may lead to dementia. The pathophysiological basis of cognitive impairment and dementia in PD is unclear. The aim of this thesis was to study the pathophysiological basis of cognitive impairment and dementia in PD. We evaluated the relation between frontostriatal dopaminergic dysfunction and the cognitive symptoms in PD patients with [18F]Fdopa PET. We also combined [C]PIB and [18F]FDG PET and magnetic resonance imaging in PD patients with and without dementia. In addition, we analysed subregional striatal [18F]Fdopa PET data to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. The impaired dopaminergic function of the frontostriatal regions was related to the impairment in cognitive functions, such as memory and cognitive processing in PD patients. PD patients with dementia showed an impaired glucose metabolism but not amyloid deposition in the cortical brain regions, and the hypometabolism was associated with the degree of cognitive impairment. PD patients had atrophy, both in the prefrontal cortex and in the hippocampus, and the hippocampal atrophy was related to impaired memory. A single 15-min scan 75 min after a tracer injection seemed to be sufficient for separating patients with PD from healthy controls in a clinical research environment. In conclusion, the occurrence of cognitive impairment and dementia in PD seems to be multifactorial and relates to changes, such as reduced dopaminergic activity, hypometabolism, brain atrophy and rarely to amyloid accumulation.Siirretty Doriast

The neurobiological basis of gait dysfunction in Parkinson’s disease: A cross-sectional and longitudinal approach

Ph. D. Thesis.Gait impairments are a cardinal feature of Parkinson’s disease (PD) and significantly affect the well-being of patients. However, current therapies are not effective at improving specific aspects of gait in PD nor preventing them from worsening over time. This is largely due to poor understanding of the mechanisms that the brain uses to control discrete gait characteristics in PD. The aim of this thesis was, therefore, to investigate associations between the brain and gait characteristics in PD, using both cross-sectional and longitudinal analytical approaches. Newly diagnosed PD participants (n=99) and age-matched controls (n=47) completed quantitative gait, structural magnetic resonance imaging and clinical assessments soon after diagnosis; additional gait assessments were completed every 18 months for up to six years. Partial correlations and linear regression analyses determined cross-sectional associations between regional brain volumes and gait. Linear mixed-effects models identified gait characteristics that changed over six years in PD, more so than in controls, and assessed the predictive nature of regional brain volumes on gait changes. Original contributions to knowledge were that regional brain volumes selectively associated with discrete gait characteristics in PD; many associations were unique to PD, even in early disease. Brain regions which primarily relate to both motor and non-motor functions correlated with PD gait impairment. Associations with non-motor structures might be attributable to contributions from the cortical cholinergic system, given its role in maintaining gait in PD. This thesis provides evidence for the reliance on alternative and compensatory neural mechanisms during PD gait. Additionally, this thesis demonstrates the first evidence for regional brain volumes predicting disease-specific changes in gait. This not only provides greater understanding of neural underpinnings of gait dysfunction in PD, but demonstrates the potential for regional brain volumes to be considered clinically as an indicator of those at greater risk of mobility loss and fallsWellcome Trust, Parkinson’s U

Effects of dance therapy on balance, gait and neuro-psychological performances in patients with Parkinson's disease and postural instability

Postural Instability (PI) is a core feature of Parkinson’s Disease (PD) and a major cause of falls and disabilities. Impairment of executive functions has been called as an aggravating factor on motor performances. Dance therapy has been shown effective for improving gait and has been suggested as an alternative rehabilitative method. To evaluate gait performance, spatial-temporal (S-T) gait parameters and cognitive performances in a cohort of patients with PD and PI modifications in balance after a cycle of dance therapy

A systematic review of the evidence that brain structure is related to muscle structure and their relationship to brain and muscle function in humans over the lifecourse

BACKGROUND: An association between cognition and physical function has been shown to exist but the roles of muscle and brain structure in this relationship are not fully understood. A greater understanding of these relationships may lead to identification of the underlying mechanisms in this important area of research. This systematic review examines the evidence for whether: a) brain structure is related to muscle structure; b) brain structure is related to muscle function; and c) brain function is related to muscle structure in healthy children and adults. METHODS: Medline, Embase, CINAHL and PsycINFO were searched on March 6th 2014. A grey literature search was performed using Google and Google Scholar. Hand searching through citations and references of relevant articles was also undertaken. RESULTS: 53 articles were included in the review; mean age of the subjects ranged from 8.8 to 85.5 years old. There is evidence of a positive association between both whole brain volume and white matter (WM) volume and muscle size. Total grey matter (GM) volume was not associated with muscle size but some areas of regional GM volume were associated with muscle size (right temporal pole and bilateral ventromedial prefrontal cortex). No evidence was found of a relationship between grip strength and whole brain volume however there was some evidence of a positive association with WM volume. Conversely, there is evidence that gait speed is positively associated with whole brain volume; this relationship may be driven by total WM volume or regional GM volumes, specifically the hippocampus. Markers of brain ageing, that is brain atrophy and greater accumulation of white matter hyperintensities (WMH), were associated with grip strength and gait speed. The location of WMH is important for gait speed; periventricular hyperintensities and brainstem WMH are associated with gait speed but subcortical WMH play less of a role. Cognitive function does not appear to be associated with muscle size. CONCLUSION: There is evidence that brain structure is associated with muscle structure and function. Future studies need to follow these interactions longitudinally to understand potential causal relationships

Measurement of allocentric processing in mild cognitive impairment and early Alzheimer’s disease using a virtual reality object location paradigm

Aim: Mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) are major contributors to disability in old age and defined in the early stages by spatial memory deficits associated with hippocampal (HC) and entorhinal (EC) atrophy. Currently diagnosis occurs late in the process which limits efficacy of interventions. This study investigated the neural correlates of a novel object location task (OLT) in immersive virtual reality (iVR). Methods: Twenty amnestic MCI (aMCI) patients and twenty two healthy controls were tested on the iVR OLT, underwent neuropsychological testing and structural MRI scanning. OLT performance and HC, EC subfield volumetric data were compared between groups, and correlational analyses of HC/EC volumes and performance were conducted. Results: Participants with aMCI were significantly impaired in object location recall and object recognition compared to controls. They had significantly smaller total HC, subiculum, CA1, EC and perirhinal volumes. There was a significant interaction of group in analysis of neural correlates: OLT performance was strongly predicted by total HC and subiculum volumes in patients only. EC subfields were not significant predictors of performance. Conclusion: Performance on the novel OLT in immersive VR is a good indicator of HC integrity in older adults with amnestic MCI and can improve the diagnostic process for people with MCI and AD in the future

Caudate nucleus volume mediates the link between cardiorespiratory fitness and cognitive flexibility in older adults

The basal ganglia play a central role in regulating the response selection abilities that are critical formental flexibility. In neocortical areas, higher cardiorespiratory fitness levels are associated with increased gray matter volume, and these volumetric differences mediate enhanced cognitive performance in a variety of tasks. Here we examine whether cardiorespiratory fitness correlates with the volume of the subcortical nuclei that make up the basal ganglia and whether this relationship predicts cognitive flexibility in older adults. Structural MRI was used to determine the volume of the basal ganglia nuclei in a group of older, neurologically healthy individuals (mean age 66 years, N = 179).Measures of cardiorespiratory fitness (VO2max), cognitive flexibility (task switching), and attentional control (flanker task) were also collected. Higher fitness levels were correlated with higher accuracy rates in the Task Switching paradigm. In addition, the volume of the caudate nucleus, putamen, and globus pallidus positively correlated with Task Switching accuracy.Nested regression modeling revealed that caudate nucleus volume was a significantmediator of the relationship between cardiorespiratory fitness, and task switching performance. These findings indicate that higher cardiorespiratory fitness predicts better cognitive flexibility in older adults through greater grey matter volume in the dorsal striatum

Investigating the relationship between cholinergic system integrity and Parkinson’s disease symptoms using MRI and EEG

Cholinergic cells of the basal forebrain (cBF) and pedunculopontine nucleus (PPN) are implicated in Parkinson’s disease (PD), but current understanding of their role in PD symptomology is limited. Neuropathological and recent in vivo imaging research implies that cBF and PPN degeneration is associated with PD cognitive and mobility impairments. There remains a need to identify and validate widely accessible markers of cholinergic system degeneration to better understand its contribution to these symptoms. The aim of this thesis was to investigate how structural changes in the cBF and PPN relate to cortical activity and cognitive and mobility performance in people with PD, people with mild cognitive impairment (MCI), and healthy age-matched controls. T1 and diffusion-weighted images were used in combination with stereotactic maps of the cBF and PPN to extract volumetric and diffusivity metrics from these regions as in vivo surrogate markers of structural integrity. These structural measures were assessed for their relationship with resting-state EEG, and cognitive and functional mobility performance. People with PD showed reduced cBF volumes compared to healthy controls, and elevated PPN diffusivity compared to people with MCI. Subregional cBF volumes correlated with EEG changes in the theta-alpha range in people with PD and people with MCI. Volume loss in the cBF was also shown to mediate the relationship between executive function and Timed Up and Go dual-task performance in people with PD. PPN diffusivity metrics demonstrated correlations with cognitive performance and EEG changes in the alpha range in people with PD, and in the beta-gamma range in people with MCI. Cortical activity measured with EEG may hold physiological relevance for structural changes occurring in the cBF and PPN. Volumetric loss in the cBF may impair the attentional-executive control of mobility functions. Elevated PPN diffusivity may impair attentional performance during tasks that require sensorimotor integration

The clinical utility of multidisciplinary rehabilitation in individuals with Huntington’s Disease

Background Huntington’s disease (HD) is a chronic neurodegenerative disorder characterised by a progressive loss of cognitive function, motor control and psychiatric features. Individuals also display a variety of systemic features. Progressive neuronal dysfunction and neuronal cell death are thought to underlie the onset and progression of many clinical features of HD. Despite scientific progress, there is still no cure or disease modifying therapy for HD, and available pharmaceutical agents only provide partial relief of motor and psychiatric features. An emerging body of evidence indicates that lifestyle enrichment may delay the onset and progression of clinical features, and exert favourable effects on neuropathological aspects of HD. Few studies have evaluated the effects of lifestyle enrichment strategies like multidisciplinary rehabilitation on the clinical features of HD. Moreover, no study has evaluated the effects of multidisciplinary rehabilitation on neuropathological aspects of HD. Aims The initial aim of this thesis was to determine factors that contribute to features of the disease that negatively impact on activities of daily living such as mobility and balance (Chapter 2), and to identify, using a literature review, a rehabilitation strategy that could positively impact on these features of HD (Chapter 3). These studies informed our ultimate aim which was to investigate the clinical utility of multidisciplinary rehabilitation on clinical and neuropathological features of HD (Chapters 4, 5 and 6) Methods In study 1 (Chapter 2), 22 participants were assessed using a battery of balance, mobility, cognitive tests, assessments of muscle strength and body composition measures. Data was . then statistically examined using stepwise linear regression to identify factors that contribute to balance and mobility impairments in individuals with manifest HD. In study 2 (Chapter 3), a systematic search of journal databases was made from inception to July 2014 for studies reporting on resistance exercise in patients with neurodegenerative disorders. Selected studies were abstracted and critically appraised using a quality control checklist. For the intervention studies, (3 and 4 Chapters 4 and 5), 20 participants with manifest HD were randomly assigned to either a control or training group. Individuals randomised to the intervention group were provided with a nine month multidisciplinary intervention comprising once weekly supervised clinical exercise, thrice weekly home based exercise and fortnightly occupational therapy, while those randomised to the control group were asked to continue with their standard care and daily activities. Participants were assessed using motor, cognitive, psychological, body composition and quality of life measures at baseline and at the completion of the intervention. In study 5 (Chapter 6), 15 participants with manifest HD were assessed using magnetic resonance imaging and a battery of cognitive assessments after nine months of multidisciplinary rehabilitation to see whether such a therapy is capable of inducing favourable changes in brain structure and cognitive function. Results The main factors that contribute to mobility and balance impairments in patients with manifest HD were found to be lower limb muscle weakness and a loss of cognitive function (Study 1). Systematic evaluation of the effects of resistance exercise for neurodegenerative disorders showed that it is beneficial for multiple sclerosis and Parkinson’s disease. In particular, improvements in muscle strength, mobility, balance, clinical disease progression, fatigue, functional capacity, quality of life, disease biology, electromyography activity, mood, skeletal muscle volume and architecture were reported in individuals with multiple sclerosis or Parkinson’s disease (PD) after resistance exercise. The most robust effects of resistance exercise were found for muscle strength outcomes, and were more pronounced in individuals with PD (Study 2). The multidisciplinary rehabilitation intervention studies conducted as part of this thesis significantly improved isometric and isokinetic muscle strength, self-perceived balance, body mass, lean tissue mass and fat mass in patients with HD (Studies 3 and 4). Moreover, multidisciplinary rehabilitation also increased grey matter (GM) volume in the caudate nucleus and dorsolateral prefrontal cortex of patients. The significant increases in GM volume were accompanied by, and correlated to, a significant improvement in performance in verbal learning and memory. Conclusions The work presented here shows that lower extremity muscle weakness and a loss of cognitive function significantly contribute to impairments in mobility and balance. This work also shows that strength training has favourable effects on motor function, including strength, mobility and balance, as well as other clinical features in similar neurodegenerative disorders, and thus should be integrated into multidisciplinary rehabilitation interventions for HD. In addition, this study provides evidence that multidisciplinary rehabilitation can significantly improve aspects of motor control, cognitive function and body composition. Finally we show, for the first time, that multidisciplinary rehabilitation can increase GM volume in structures known to degenerate in HD, and that such increases are functionally related to changes in verbal learning and memory. Future work is urgently required to confirm and expand on these exciting findings, particularly with respect to the neurorestorative properties of multidisciplinary rehabilitation

Associations between Mobility, Cognition, and Brain Structure in Healthy Older Adults.

Mobility limitations lead to a cascade of adverse events in old age, yet the neural and cognitive correlates of mobility performance in older adults remain poorly understood. In a sample of 387 adults (mean age 69.0 ± 5.1 years), we tested the relationship between mobility measures, cognitive assessments, and MRI markers of brain structure. Mobility was assessed in 2007-2009, using gait, balance and chair-stands tests. In 2012-2015, cognitive testing assessed executive function, memory and processing-speed; gray matter volumes (GMV) were examined using voxel-based morphometry, and white matter microstructure was assessed using tract-based spatial statistics of fractional anisotropy, axial diffusivity (AD), and radial diffusivity (RD). All mobility measures were positively associated with processing-speed. Faster walking speed was also correlated with higher executive function, while memory was not associated with any mobility measure. Increased GMV within the cerebellum, basal ganglia, post-central gyrus, and superior parietal lobe was associated with better mobility. In addition, better performance on the chair-stands test was correlated with decreased RD and AD. Overall, our results indicate that, even in non-clinical populations, mobility measures can be sensitive to sub-clinical variance in cognition and brain structures

Sarcopenia and cognitive ageing: investigating their interrelationship, biological correlates and the role of glucocorticoids

Background Sarcopenia and age-related cognitive decline (ARCD) are important age-related conditions which significantly impact upon the quality of life of older adults. ARCD is a well-established research area, whereas sarcopenia is a relatively new field. Research into the inter-relationships between them and possible common underlying mechanistic processes is lacking. Methods Several research techniques were used: a large systematic review; the development of an image analysis technique to measure neck muscle size on volumetric MR brain scans; the subsequent use of the technique in elderly cohort studies; statistical modelling to investigate the role of glucocorticoids in sarcopenia; and an invasive clinical study to develop a novel technique to measure the activity of 11beta-hydroxysteroid dehydrogenase (11βHSD1) in the human brain in vivo. Results I consistently found a relationship between: some measures of brain structure and muscle size; markers of brain structure and muscle function, mostly grip strength and gait speed; and cognition and muscle function. However, I found no relationship between current cognition and muscle size in any of the above studies. Cortisol was identified as a possible explanatory factor in the relationship between both cognition and brain volume with gait speed. I found an association between markers of immunosenescence and sarcopenia (neck muscle CSA and grip strength) and an association between expression of the cortisol amplifying enzyme 11βHSD1 and quadriceps strength. I developed a technique to measure 11βHSD1 activity across the human brain, which found that the amount of cortisol produced within the brain was not detectable and highlighted the asymmetries within the cerebrovascular venous system. Conclusions Further longitudinal studies looking at the association between sarcopenia and ARCD are now required to investigate these important relationships further and hopefully this will lead to improved therapeutic options